Cancer immunology

Cancer Immunology- basics

1. d r THANGAM.V I MVsc CANCER IMMUNOLOGY

2. CANCER OR NEOPLASIA A new growth of abnormal tissue that is often uncontrolled and progressive.

3. CANCER CELLS Immune system views cancer cells as “Self altered cells that have excaped normal growth regulating mechanism” Production of new cells in our body is regulated so as to maintain the number of any particular cell When certain cells no longer respond to normal growth-control mechanisms it leads to neoplasm or cancer

4. CLASSIFICATION OF TUMORS

5. HISTORY OF CANCER IMMUNOLOGY Paul Ehrlich conceived the idea that tumor cells can be recognized as foreign and eliminated by the immune system

6. HISTORY OF CANCER IMMUNOLOGY In 1957 Burnet and Thomas coined the term immune surveillance which implies that the normal function of the immune system is to scan the body for emerging malignant cells and destroy them

7. IMMUNE SYSTEM IS BOTH A CANCER PROMOTER AND SUPPRESSOR

8. How does immune cells identify tumor or cancer cells? Cancer cells express tumour -associated antigens (TAAs) or tumour -specific antigens (TSAs) that can be recognised by the immune system as foreign elements. Decreased expression of MHC’s Lipid assymetry of cancer cells Phosphatidylethanolamine (PE), a lipid membrane component which exists only in the inner leaflet of cell membrane under normal circumstances, has increased surface representation on the outer membrane in cancer cells

9. INNATE IMMUNITY Alterations in the cancer cells (changes in the composition of their cell surface proteins) expression of tumor-associated antigens recognized by complement proteins complement-mediated death

10. Activation of complement proteins has been reported in local and/or systemic biological fluids of cancer patients AND cancer tissues from patients diagnosed with neuroblastoma , lung cancer, ovarian cancer, and a variety of others

11. Expression of MHC class I becomes altered or reduced in cancer cells activation of NK cells via activating receptors present on NK cell surface Nk cell surface receptors bind to surface glycoproteins present on the tumors programmed cell death occurs by tumor-necrosis factor-alpha- (TNF- α -) dependent release of cytoplasmic granules perforin and granzymes form pores in cell membranes

12. NEUTROPHILS PROMOTE CANCER SYNTHESIS  Proteases such as neutrophil elastase present in neutrophil granules facilitate growth of cancer cells Other proteases in the neutrophil granules assist in cleaving extracellular matrix proteins, thus allowing cancer invasion and metastasis

13. ADAPTIVE IMMUNITY Formation of neoantigens , due to tumorigenesis / oncogenesis phagocytosed by antigen-presenting cells (APCs) or pinocytosed by dendritic cells for antigen processing MHC class II molecules present exogenous peptides of tumor antigens, MHC class I molecules present endogenous peptides derived from cancer antigens on the APC to the antigen-specific T cell receptor on CD4 +  T cells or CD8 +  T cells

14. Activation of CD4 +  T cells by MHC class II on APC primes them for subsequent exposures to that particular antigenic peptide/MHC class II complex, thus forming memory T cells IL-2 is also produced when T cells are activated and further promotes T cell proliferation   cytolytic  T cell-mediated lysis of cancer cells 

15. CANCER IMMUNOEDITING

16. How cancers solve the challenge of host immunity

17. Cancers can overwhelm the host immune system Malignancies outrace the host immune system No sufficient time for manipulation of the host immune response to achieve meaningful therapeutic benefits CANCER IMMUNE SYSTEM

18. Cancers can hide from the immune system By losing target antigen expression By reducing antigen presentation by diminshed expression of MHC class I or class II on malignant cells or APC’s through disordered angiogenesis and dense collagenous stroma

19. CANCERS CAN SUBVERT THE IMMUNE SYSTEM Malignant cells can secrete cytokines to create an immune suppressive microenvironment Anticytokine antibodies can target these immunosuppressive networks

20. CANCER CAN DEFEND AGAINST T CELL ASSAULTS Immune checkpoints are used by cancers to deactivate T cells

21. CANCER CELLS CAN ERECT SHIELD TO DEFLECT IMMUNE SYSTEM T cells that cannot infiltrate into tumors cannot exert significant antitumor effects Cancer may shed antigens into the tumor microenvironment thereby diverting T- cells

22. Presence of soluble and membrane-bound complement regulatory proteins (CRPs) inhibit various steps in the multiple complement signaling pathways protecting cancer cells against complement-mediated injury  PD-1 and PD-L1 are types of proteins found on cells in body. PD‑1 protein is found on immune cells called T cells. It normally acts as a type of "off switch" that helps in keeping the T cells from attacking other cells in the body. PD-1 attaches to PD‑L1, a protein found on some normal (and cancer) cells. This interaction basically tells the T cell to leave the other cell alone and not attack it. Some cancer cells have large amounts of PD‑L1, which helps them hide from immune attack.

23. IMMUNOTHERAPY  Stimulation of the immune system to treat cancer, improving on the system's natural ability to fight cancer

24. NON SPECIFIC IMMUNE STIMULATION Drugs are given that increase the overall immune response of the body For example a patient suffering from bladder cancer after removal of the cancerous part in the bladder lining is given BCG Bacillus Calmette -Guerin (BCG) is the main intravesical immunotherapy for treating early-stage bladder cancer. The body’s immune system cells are attracted to the bladder and activated by BCG, which in turn affects the bladder cancer cells.

25. T – CELL TRANSFER THERAPY A sample of T cells is taken from the blood through a process called apheresis . First a tube is put into a vein in each arm. One tube removes the blood and passes it into an apheresis machine. The machine takes out only T cells and the rest of blood cells and normal blood fluid go back into your body through the tube in other arm. In the lab, they change the T cells by genetically engineering the T cell.

26. The T cell is now a CAR T-cell. CAR stands for chimeric antigen receptor. These CAR T-cells are designed to recognise and target a specific protein on the cancer cells. These changed T cells are grown and multiplied in the lab. Once there are enough cells grown a drip containing these cells are put back into bloodstream The aim is for the CAR T-cells to then recognise and attack the cancer cells.

27. IMMUNE CHECKPOINT INHIBITORS checkpoints – molecules on certain immune cells that need to be activated (or inactivated) to start an immune response . PD-1 or PD-L1 CTLA-4

28. DRUGS THAT TARGET PD-1 OR PD-L1 PD-1 is a checkpoint protein on T cells which normally acts as a type of “off switch” that helps in keeping the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1 present in cancer cells , it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells.

29. Drugs that target CTLA-4 CTLA-4 is another protein on some T cells that acts as a type of “off switch” to keep the immune system in check. Monoclonal antibodies that target CTLA-4 will be helpful in treating cancers

30. MONOCLONAL ANTIBODIES Monoclonal antibodies  ( mAb or moAb ) are  antibodies  that are all clones of a unique parent cell.  Monoclonal antibodies  can have monovalent affinity, in that they bind to the same epitope Monoclonal antibodies attach to specific proteins on cancer cells. This flags the cells so the immune system can find and destroy those cells.

31. CANCER VACCINES Antigen vaccines These vaccines are made from special proteins (antigens) in cancer cells. Scientists have worked out the genetic codes of many cancer cell proteins Whole cell vaccines A whole cell vaccine uses the whole cancer cell, not just a specific cell protein (antigen), to make the vaccine

32. Dendritic cell vaccines Dendritic cells help the immune system  recognise and attack abnormal cells, such as cancer cells. DNA vaccines These vaccines are made with DNA from cancer cells.